The focus of this application is on the developmental consequences for children exposed to stress during gestation. One of the major placental stress signals in pregnant primates is the peptide corticotrophin-releasing hormone (CRH). This peptide plays a key role in the maturation of the fetal hypothalamic-pituitary-adrenal (HPA) axis and it synchronizes events that underlie fetal growth and maturation. Placental CRH is responsive to all the major biological signals of stress in the maternal and fetal compartments. Stress-related alterations in the normal pattern of placental CRH production during pregnancy have major implications for childhood development. Extensive research supports the conclusion that placental CRH is the stress index consistently associated with birth outcomes, however placental CRH has not been used to predict neurodevelopmental outcomes. The focus on placental CRH capitalizes on a direct index of fetal experience and avoids the assumption that maternal stress results in a coherent and consistent maternal physiological profile that is transmitted to the fetus. We propose to assess 600 children (between the ages of 6-0 and 7-11 years) for whom we have extensive histories of prenatal stress exposure and birth phenotypes with measures of (a) emotional regulation;(b) cognition;(c) anatomy of brain structures (using structural magnetic resonance imaging (MRI);and (d) regulation of the HPA stress axis. Influences of prenatal CRH on emotional regulation (Aim 1) will be evaluated by examining the relation between levels of CRH with measures of parent and self-report of temperament. Programming effects of early exposure to CRH on cognition (Aim 2) will be evaluated by examining the relation between levels of placental CRH and performance on standardized measures of intelligence and novel measures of attention, memory and executive function. The effects of prenatal exposure to CRH on the volume of the hippocampus, amygdala and prefrontal cortex (Aim 3) will be evaluated in a subgroup of 80 children in the upper and lower quintile of third trimester CRH level. Prenatal influences of CRH on HPA reactivity (Aim 4) will be evaluated by assessing salivary cortisol at rest and after mild stress. These studies in children are the first to examine the role of prenatal CRH on human development.